DESCRIPTION: Airway smooth muscle is innervated by excitatory and inhibitory autonomic nerves. In humans autonomic nerve-induced constriction of the airways is mediated by acetylcholine while the predominant relaxant innervation of airway smooth muscle is neither adrenergic nor cholinergic in nature and has been described as the nonadrenergic, noncholinergic or NANC relaxant innervation. The counteracting actions of these autonomic nerves play a primary role in regulating airway smooth muscle tone and are thus likely to be integral effectors of lung physiology and pathophysiology. It is my long-term objective to develop a more thorough understanding of the autonomic control of the airways. It has been proposed that the NANC relaxant nerves serve as a brake on the cholinergic nerves of airways, preventing excessive constriction during periods of elevated parasympathetic (cholinergic) tone. It has been further proposed that dysfunction of these relaxant nerves might contribute to the pathogenesis of pulmonary disease. Despite this possibility and their role as the primary relaxant nerves of the airways, very little is known about the regulation of the NANC relaxant innervation of the lung. The central hypothesis to be addressed in this proposal is that the NANC relaxant nerves are anatomically and physiologically distinct from all other autonomic nerves innervating airway smooth muscle and consequently, may be regulated in a way that is entirely different from that of the other nerves innervating the lung. Further, it is asserted that any attempt to define the role of these nerves in regulating airway tone will require a better understanding of their anatomical and physiological attributes. To this end, a multidisciplinary approach will be employed to thoroughly characterize the morphological and physiological attributes of the NANC relaxant nerves of guinea pig airways. In addition, using both intracellular electrophysiological recording techniques and an in vivo model to study airway reflexes, some fundamental aspects of their regulation both at the level of the parasympathetic ganglia and through centrally-mediated reflexes will be defined. It is anticipated that this information will improve our understanding of the role of the autonomic innervation of the healthy and diseased lung.